Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16](O)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.[NH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]([CH3:50])[C:45]([O:47][CH2:48][CH3:49])=[O:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]([CH3:50])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C)CCCCN
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)CCCCNC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At RT, 72 μl (0.415 mmol) of DIEA were added to a solution of 148 mg (0.377 mmol) of (+)-cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid and 98 mg (about 0.66 mmol, crude material) of ethyl 6-amino-2-methylhexanoate in 1.0 ml of DMF. The resulting mixture was cooled to 0° C., and four portions of altogether 186.4 mg (0.49 mmol) of HATU were then added. The reaction mixture was slowly warmed to RT, stirred at RT for 16 h and then added to water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by preparative RP-HPLC (acetonitrile/water gradient) gave 134.0 mg (64.9% of theory) of the target compound as a diastereomer mixture.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O)=[CH:5]1)(=O)C.[N+:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(O)(=O)C>[N+:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(=O)n1cc(O)c2ccccc21
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Nc2c[nH]c3ccccc23)cc1
Temperature: 25 °C

Procedure:
More in particular, to a mixture of N-acetyl-3-hydroxyindole (a) (0.114 mol, 20 g) in acetic acid (150 ml), was added 4-nitroaniline (1.5 equiv., 0.171 mol, 23.65 g). The mixture was heated at reflux for 5 hours and cooled to room temperature. An orange precipitate was filtered off and washed with isopropanol and diisopropyl ether, affording intermediate b.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: Oc1ccc(F)cc1
Product: Cc1cccc(Oc2ccc(F)cc2)c1C(=O)O

Procedure:
The title compound was synthesized from 2-chloro-6-methyl-benzoic acid and 4-fluorophenol in analogy to example 18a; MS-(−)-ion: M−1=245.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CO>[Pd].CCO.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH2:17])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: COC(=O)c1cc(C(=O)OC(C)(C)C)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Yield: 71.2 %

Procedure:
A mixture of 5-nitro-isophthalic acid 1-tert-butyl ester 3-methyl ester (D78) (5.3 g, 19 mmol, 1 equiv), NH4COOH (11.9 g, 190 mmol, 10 equiv) and 10% Palladium on charcoal (50% wet, 0.75 g, 7% w/w) in EtOH (50 ml) and H2O (25 ml) was heated at 50° C. for 30 min. MeOH (20 ml) was added and the resulting solution was heated at 50° C. for another hour then cooled to room temperature, filtered through a pad of celite and concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO3 solution (100 ml) and the aqueous phase was extracted with AcOEt (150 ml). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane to give of 5-amino-isophthalic acid 1-tert-butyl ester 3-methyl ester (D79) (3.4 g, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[C:3]=1[Cl:13].[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31](B(O)O)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl>[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31]([C:9]3[CH:8]=[N:7][C:6]([NH2:11])=[C:5]4[O:12][C:2]([Cl:1])=[C:3]([Cl:13])[C:4]=34)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(B(O)O)cn2)CC1
Reactant: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)c(Cl)c34)cn2)CC1
Temperature: 75 °C

Procedure:
A mixture of 2,3-dichloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (500 mg, 1.52 mmol), [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]boronic acid (542 mg, 1.67 mmol) (1,1′-bis-(diphenylphosphine)-ferrocene) palladium dichloride (111 mg, 0.152 mmol) and potassium carbonate (525 mg, 3.80 mmol) in 1,4-dioxane (5.06 mL) and water (2.2 mL) was heated to 75° C. for 2 h. The reaction mixture was concentrated, suspended in ethyl acetate (10 mL), filtered through a pad of Celite, and concentrated onto silica gel. Purification by ISCO chromatography (5 to 50% acetone:heptane) afforded 437 mg (51%) of the title compound as a red-brown solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1 H), 7.65 (d, J=0.5 Hz, 1 H), 7.57 (d, J=0.8 Hz, 1 H), 5.03 (br. s., 2 H), 3.99-4.41 (m, 1 H), 3.54-3.86 (m, 1 H), 2.14-2.42 (m, 2 H), 2.03 (dd, J=14.4, 3.5 Hz, 2 H), 1.81-1.96 (m, 2 H), 1.45-1.64 (m, 2 H), 0.91 (s, 9 H), 0.05-0.17 (m, 6 H); MS (APCl): 481.31, 483.37 [M+H]+; HPLC tR=3.99 min (ZQ3: nonpolar—4 min).
Reaction SMILES: [OH:1][C:2]([CH3:30])([CH3:29])[C:3]#[C:4][C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4>C(O)C.CN(C)C(=O)C.[Pd]>[OH:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:23])([CH3:24])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4
Reactant: COc1cc2c(cc1C#CC(C)(C)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: COc1cc2c(cc1CCC(C)(C)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1, 21.0 mg, 0.0527 mmol) was dissolved in ethanol (15 mL) and N,N-dimethylacetamide (2 mL), added with 10% Pd/C (6.7 mg), and then stirred at room temperature overnight under hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The resulting residues were diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was washed with dichloromethane to obtain the title compound (yellow powder, 16.9 mg, 80%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[C:14]([O:18][C:19](=[O:35])[NH:20][C@@H:21]([CH:33]=O)[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)([CH3:17])([CH3:16])[CH3:15].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O.C(O)(=O)C>[C:14]([O:18][C:19](=[O:35])[NH:20][C@@H:21]([CH2:33][NH:5][C@@H:4]([C:3](=[O:13])[NH:2][CH3:1])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc2ccccc2c1
Reactant: CNC(=O)[C@H](N)Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](Cc1ccccc1)NC[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
D-Phenylalanine-N-methyl amide (1.50 g, 8.35 mmol) and (1R)-1-formyl-2-(2-naphthyl)ethylcarbamic acid tert-butyl ester (2.50 g, 8.35 mmol) were dissolved in methanol (40 ml). Molsieves (3 Å, 30 g) and acetic acid (3 ml) were added and the mixture was cooled with ice and sodium cyanoborohydride (0.80 g, 12.5 mmol) was added. The mixture was stirred overnight at room temperature. Water (30 ml) and saturated aqueous sodium hydrogen carbonate (30 ml) were added and the mixture was extracted with methylene chloride (3×40 ml). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 1.19 g of ((1R)-1-(((1R)-1-methylcarbamoyl-2-phenylethylamino)methyl)-2-(2-naphthyl)ethyl)carbamic acid tert butyl ester
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.[OH-:30].[Na+]>CC(CC)=O.O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][N:17]=[C:16]2[O:30][C:2]1[CH:7]=[CH:6][C:5]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1N1CCOCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1cc2ncnc(Oc3ccc(Nc4ccccc4N4CCOCC4)cc3)c2cc1OC
Reaction time: 4 h
Yield: 113.3 %

Procedure:
3-Fluoro4-nitrophenol (300 mg), morpholine (800 μl), and calcium carbonate (50 mg) were added to dimethylformamide (3 ml), and the mixture was heated at 130° C. for 12 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 3-morpholino-4-nitrophenol (400 mg, yield 94%). The resultant 3-morpholino-4-nitrophenol (400 mg) was added to dimethylformamide (3 ml). Palladium hydroxid-carbon (110 mg) and hydrogen were added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was then purified by chromatography on silica gel using chloroform/acetone for development to give 4-amino-3-morpholinophenol (296 mg, yield 85%). The resultant 4-amino-3-morpholinophenol (296 mg), 4-chloro-6,7-dimethoxyquinazoline (479 mg), and n-tetraethylammonium bromide (244 mg) were dissolved in ethyl methyl ketone (10 ml) to prepare a solution. A solution (10 ml) of sodium hydroxide (479 mg) in water was added to the solution, and the mixture was sitrred at 80° C. for 4 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated. The residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (396 mg, yield 68%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH:23]=[CH2:24])[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
To a solution of N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (2 g) in dimethylformamide (6 mL) was added tributyl(vinyl)tin (3.63 g), 2,6-di-tert-butyl-4-methylphenol (50 mg) and dichlorobis(triphenylphosphine)palladium (0.25 g). The reaction was heated at 80° C. under nitrogen for 6 hours and then cooled to room temperature. The mixture was filtered through diatomaceous earth and poured into water and dichloromethane. The organic layer was separated and the aqueous was further extracted with dichloromethane. The combined organic layers were dried, filtered and evaporated. Purification (SiO2, methanol:dichloromethane 5:95 as eluant) gave the sub-titled compound (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([CH3:17])=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:15]([CH3:17])[CH3:14])[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (1 equiv.) in methanol (5 mL), acetone (5 equiv.) and acetic acid (2 equiv.) were added and reaction mixture stirred at room temperature for 2 h. Then NaBH3CN (3 equiv.) was added at 0° C. The resulting reaction mixture was stirred further for 16 h at room temperature. On completion, solvent was evaporated and water added to the residue and the extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford crude product which was used in next step without further purification (yield 80-90%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 4-fluorobenzaldehyde and 4-Chloro-3-(trifluoromethyl)phenol. LC-MS (ESI): m/z 301 [M+H]+; 3.76 min (ret time).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]([CH3:22])[C:16]([CH3:21])([C:18]([OH:20])=O)[CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:54][O:55][C@@H:56]([C@@H:73]1[CH2:77][CH2:76][CH2:75][N:74]1[C:78](=[O:97])[CH2:79][C@@H:80]([O:95][CH3:96])[C@@H:81]([N:86]([CH3:94])[C:87](=[O:93])[C@H:88]([CH:90]([CH3:92])[CH3:91])[NH2:89])[C@@H:82]([CH3:85])[CH2:83][CH3:84])[C@@H:57]([CH3:72])[C:58]([NH:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:59]>ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]([CH3:22])[C:16]([CH3:17])([C:18]([NH:89][C@H:88]([C:87]([N:86]([C@@H:81]([C@@H:82]([CH3:85])[CH2:83][CH3:84])[C@H:80]([O:95][CH3:96])[CH2:79][C:78]([N:74]1[CH2:75][CH2:76][CH2:77][C@H:73]1[C@H:56]([O:55][CH3:54])[C@@H:57]([CH3:72])[C:58]([NH:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:59])=[O:97])[CH3:94])=[O:93])[CH:90]([CH3:91])[CH3:92])=[O:20])[CH3:21])=[O:14]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN(C(=O)CCCCCN1C(=O)C=CC1=O)C(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of #249 (382 mg, 1.23 mM) in 5 mL of dichloromethane, HATU (482 mg, 1.23 mM) was added followed by triethylamine (0.52 mL, 1.23 mM). The reaction was allowed to stir for 1 hour at room temperature followed by the addition of #250 (762 mg, 1.23 mM). The reaction was allowed to stir for 3 hours. Reaction was concentrated in vacuo. Reverse phase purification (MethodL) followed by lyophilization yielded a white solid mc#120 (124 mg, 11%). HPLC (Protocol A at 45° C.;) m/z 911.5 [M+H+], retention time=9.676 minutes.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7](C(OC)=O)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH3:14][Mg]Br.C([O:19][CH2:20][CH3:21])C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([C:20]([OH:19])([CH3:21])[CH3:14])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CCc1ccc(C(=O)OC)cc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1ccc(C(C)(C)O)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-allylbenzoate (5.66 g, 32.1 mmol) in tetrahydrofuran (37 mL) at 0° C. under an argon atmosphere was charged with a solution of methyl magnesium bromide in diethyl ether (3 M, 26.8 mL, 80 mmol). The reaction mixture was allowed to warm to room temperature and then it was cooled to 0° C. after an additional four hours, at which time a saturated aqueous ammonium chloride solution (50 mL) was added slowly followed by diethyl ether (100 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (2×50 mL) The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:17]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:1].[ClH:1].[CH:17]1([N:22]2[CH2:23][CH2:24][N:25]([C:2]3[N:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[CH2:26][CH2:27]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(=O)c1ccc(-c2ccc(Cl)nc2)cc1
Reactant: C1CCC(N2CCNCC2)C1
Product: CC(=O)c1ccc(-c2ccc(N3CCN(C4CCCC4)CC3)nc2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-acetylphenyl)pyridine and 1-cyclopentylpiperazine.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[NH:3]1.O.NN>C(O)C>[NH2:13][CH2:12][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[N:9][CH:10]=2
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ncncc2c(=O)[nH]1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nc2ncncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A suspension of 2-(4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-ylmethyl)-isoindole-1,3-dione (50 mg, 0.163 mmol) and hydrazine monohydrate (0.25 mL, 5.09 mmol) in ethanol (3 mL) was stirred at ambient temperature for 4 hours. A light yellow solid of 2-amino-isoindole-1.3-dione was filtered off, the filtrate was evaporated and purified by column chromatography (silica gel, EtOAc/MeOH, 1/1) to yield 2-aminomethyl-3H-pyrimido[4,5-d]pyrimidin-4-one (24 mg, 83%) as a off-white solid. MS (m/e): 176.2 [M−H−].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Cc1cccc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Cc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-fluorobenzyl)benzoic acid (step 3) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.00–7.96 (2H, m), 7.36–7.14 (6H, m), 6.90–6.74 (3H, m), 5.93 (1H, d, J=7.3 Hz), 5.20 (1H, dq, J=7.3, 7.0 Hz), 4.12 (2H, s), 3.92 (3H, s), 1.44 (3H, d, J=7.0 Hz); MS (ESI) m/z 426 (M+H)+, 424 (M−H)−.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([Cl:32])=[C:23]([Cl:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: Clc1ccc(CCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 3,4-dichlorophenethyl bromide (0.27 g--see Preparation 14), anhydrous potassium carbonate (0.4 g) and acetonltrile (10 ml) was heated under reflux for 4 hours. On cooling to room temperature, water (40 ml) was added and the resulting mixture extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 7%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.22 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=1.[I:14]I.Cl>C1COCC1>[I:14][C:6]1[N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: II
Reactant: Cc1ccn2ncc(C(=O)O)c2c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(I)n2ncc(C(=O)O)c2c1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (2.11 g) in THF (40 mL) was added 1M lithiumhexadisilazide THF solution (35.9 mL) at 0° C., the mixture was stirred for 30 min, and iodine (3.65 g) was added thereto. The reaction mixture was stirred overnight at room temperature under nitrogen gas atmosphere, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium thiosulfate solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane/IPE to give the title compound (3.42 g).